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Novel Receptor for Advanced Glycation End Products‐Blocking Antibody to Treat Diabetic Peripheral Artery Disease
BACKGROUND: Expression of receptor for advanced glycation end products (RAGE) plays an important role in diabetic peripheral artery disease. We proposed to show that treatment with an antibody blocking RAGE would improve hind limb perfusion and muscle viability in diabetic pig with femoral artery (F...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955479/ https://www.ncbi.nlm.nih.gov/pubmed/33327730 http://dx.doi.org/10.1161/JAHA.120.016696 |
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author | Johnson, Lynne L. Johnson, Jordan Ober, Rebecca Holland, April Zhang, Geping Backer, Marina Backer, Joseph Ali, Ziad Tekabe, Yared |
author_facet | Johnson, Lynne L. Johnson, Jordan Ober, Rebecca Holland, April Zhang, Geping Backer, Marina Backer, Joseph Ali, Ziad Tekabe, Yared |
author_sort | Johnson, Lynne L. |
collection | PubMed |
description | BACKGROUND: Expression of receptor for advanced glycation end products (RAGE) plays an important role in diabetic peripheral artery disease. We proposed to show that treatment with an antibody blocking RAGE would improve hind limb perfusion and muscle viability in diabetic pig with femoral artery (FA) ligation. METHODS AND RESULTS: Purpose‐bred diabetic Yucatan minipigs with average fasting blood sugar of 357 mg/dL on insulin to maintain a glucose range of 300 to 500 mg/dL were treated with either a humanized monoclonal anti‐RAGE antibody (CR‐3) or nonimmune IgG. All pigs underwent intravascular occlusion of the anterior FA. Animals underwent ((201)Tl) single‐photon emission computed tomography/x‐ray computed tomography imaging on days 1 and 28 after FA occlusion, angiogenesis imaging with [(99m)Tc]dodecane tetra‐acetic acid–polyethylene glycol–single chain vascular endothelial growth factor (scVEGF), muscle biopsies on day 7, and contrast angiogram day 28. Results showed greater increases in perfusion to the gastrocnemius from day 1 to day 28 in CR‐3 compared with IgG treated pigs (P=0.0024), greater uptake of [99mTc]dodecane tetra‐acetic acid‐polyethylene glycol‐scVEGF (scV/Tc) in the proximal gastrocnemius at day 7, confirmed by tissue staining for capillaries and vascular endothelial growth factor A, and less muscle loss and fibrosis at day 28. Contrast angiograms showed better reconstitution of the distal FA from collaterals in the CR‐3 versus IgG treated diabetic pigs (P=0.01). The gastrocnemius on nonoccluded limb at necropsy had higher (201)Tl uptake (percentage injected dose per gram) and reduced RAGE staining in arterioles in CR‐3 treated compared with IgG treated animals (P=0.04). CONCLUSIONS: A novel RAGE‐blocking antibody improved hind limb perfusion and angiogenesis in diabetic pigs with FA occlusion. Contributing factors are increased collaterals and reduced vascular RAGE expression. CR‐3 shows promise for clinical treatment in diabetic peripheral artery disease. |
format | Online Article Text |
id | pubmed-7955479 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-79554792021-03-17 Novel Receptor for Advanced Glycation End Products‐Blocking Antibody to Treat Diabetic Peripheral Artery Disease Johnson, Lynne L. Johnson, Jordan Ober, Rebecca Holland, April Zhang, Geping Backer, Marina Backer, Joseph Ali, Ziad Tekabe, Yared J Am Heart Assoc Original Research BACKGROUND: Expression of receptor for advanced glycation end products (RAGE) plays an important role in diabetic peripheral artery disease. We proposed to show that treatment with an antibody blocking RAGE would improve hind limb perfusion and muscle viability in diabetic pig with femoral artery (FA) ligation. METHODS AND RESULTS: Purpose‐bred diabetic Yucatan minipigs with average fasting blood sugar of 357 mg/dL on insulin to maintain a glucose range of 300 to 500 mg/dL were treated with either a humanized monoclonal anti‐RAGE antibody (CR‐3) or nonimmune IgG. All pigs underwent intravascular occlusion of the anterior FA. Animals underwent ((201)Tl) single‐photon emission computed tomography/x‐ray computed tomography imaging on days 1 and 28 after FA occlusion, angiogenesis imaging with [(99m)Tc]dodecane tetra‐acetic acid–polyethylene glycol–single chain vascular endothelial growth factor (scVEGF), muscle biopsies on day 7, and contrast angiogram day 28. Results showed greater increases in perfusion to the gastrocnemius from day 1 to day 28 in CR‐3 compared with IgG treated pigs (P=0.0024), greater uptake of [99mTc]dodecane tetra‐acetic acid‐polyethylene glycol‐scVEGF (scV/Tc) in the proximal gastrocnemius at day 7, confirmed by tissue staining for capillaries and vascular endothelial growth factor A, and less muscle loss and fibrosis at day 28. Contrast angiograms showed better reconstitution of the distal FA from collaterals in the CR‐3 versus IgG treated diabetic pigs (P=0.01). The gastrocnemius on nonoccluded limb at necropsy had higher (201)Tl uptake (percentage injected dose per gram) and reduced RAGE staining in arterioles in CR‐3 treated compared with IgG treated animals (P=0.04). CONCLUSIONS: A novel RAGE‐blocking antibody improved hind limb perfusion and angiogenesis in diabetic pigs with FA occlusion. Contributing factors are increased collaterals and reduced vascular RAGE expression. CR‐3 shows promise for clinical treatment in diabetic peripheral artery disease. John Wiley and Sons Inc. 2020-12-17 /pmc/articles/PMC7955479/ /pubmed/33327730 http://dx.doi.org/10.1161/JAHA.120.016696 Text en © 2020 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Research Johnson, Lynne L. Johnson, Jordan Ober, Rebecca Holland, April Zhang, Geping Backer, Marina Backer, Joseph Ali, Ziad Tekabe, Yared Novel Receptor for Advanced Glycation End Products‐Blocking Antibody to Treat Diabetic Peripheral Artery Disease |
title | Novel Receptor for Advanced Glycation End Products‐Blocking Antibody to Treat Diabetic Peripheral Artery Disease |
title_full | Novel Receptor for Advanced Glycation End Products‐Blocking Antibody to Treat Diabetic Peripheral Artery Disease |
title_fullStr | Novel Receptor for Advanced Glycation End Products‐Blocking Antibody to Treat Diabetic Peripheral Artery Disease |
title_full_unstemmed | Novel Receptor for Advanced Glycation End Products‐Blocking Antibody to Treat Diabetic Peripheral Artery Disease |
title_short | Novel Receptor for Advanced Glycation End Products‐Blocking Antibody to Treat Diabetic Peripheral Artery Disease |
title_sort | novel receptor for advanced glycation end products‐blocking antibody to treat diabetic peripheral artery disease |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955479/ https://www.ncbi.nlm.nih.gov/pubmed/33327730 http://dx.doi.org/10.1161/JAHA.120.016696 |
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